A randomized, double‐blind, placebo‐controlled study of the kappa opioid receptor antagonist, CERC‐501, in a human laboratory model of smoking behavior

Abstract

Preclinical data indicate that selective kappa opioid receptor antagonists reduce nicotine self‐administration and withdrawal symptoms. The aim of the current study was to determine whether treatment with CERC‐501, an orally available, potent, and selective kappa opioid receptor antagonist, could alleviate nicotine withdrawal and craving and mitigate mood alterations associated with nicotine withdrawal in humans. Healthy, adult cigarette smokers were enrolled into this randomized, multisite, double‐blind, placebo‐controlled, crossover study. Participants completed two 8‐day treatment phases during which they received either CERC‐501 (15 mg, p.o., once daily) or placebo. On the seventh day of each dosing phase, participants were admitted as inpatients for an 18‐hour cigarette abstinence period followed by experimental testing. The primary outcome measures were (a) performance on the McKee Smoking Lapse test (ie, latency to smoke in exchange for money) and (b) number of cigarettes self‐administered during a 60‐minute ad lib smoking period. Other outcomes included measures of craving, mood, anxiety, nicotine withdrawal, and subjective effects of cigarette smoking. A total of 71 participants who smoked an average of approximately 23 cigarettes per day were enrolled, and 56 subjects completed the study. CERC‐501 was well tolerated, but it did not significantly alter the latency to start smoking (CERC‐501: 16.5 min vs placebo: 17.7 min) or the number of cigarettes smoked (CERC‐501: 3.3 cigarettes vs placebo: 3.1 cigarettes). Compared with placebo, CERC‐501 also did not affect cigarette craving, mood, anxiety, nicotine withdrawal, or subjective effects of smoking. These findings do not support a role for CERC‐501 in the treatment of nicotine use disorder.

Profile of a short-acting κ-antagonist, LY2795050, on self-grooming behaviors, forced swim test and locomotor activity: sex comparison in mice

“…Of translational relevance, the antagonist LY2795050 is used as a κ-receptor radiotracer in humans (de Laat et al, 2019; Naganawa et al, 2015a), and some studies have detected decreased occupancy in several brain regions in female compared to male humans (Vijay et al, 2016). Novel short-acting κ-antagonists have reached the clinical investigation stage, for example in persons with cocaine or tobacco use disorders, as well as mood disorders (Guerrero et al, 2019a; Jacobson et al, 2020a; Jones et al, 2019; Reed et al, 2017).…”

“…More recently, structurally novel κ-antagonists have been described with rapid onset (e.g., approximately 30 min) and moderate durations of action (e.g., approximately 24 h) in vivo (Guerrero et al, 2019b; Rorick-Kehn et al, 2014). Several compounds of this type, including LY2456302 (also known as CERC-501 or aticaprant) ((S)-3-fluoro-4-(4-((2 (3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy) benzamide), have been examined in humans, including normal volunteers, as well as persons with specific psychiatric diagnoses, such as cocaine dependence (Chang et al, 2011; Guerrero et al, 2019b; Jones et al, 2019; Lowe et al, 2014; Naganawa et al, 2015a; Reed et al, 2017).…”

The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research

“…Furthermore, CERC-501 (i.e. LY2456301) failed to attenuate cigarette smoking, craving, or nicotine withdrawal in humans (Jones et al 2019). Moreover, a recent positron emission tomography study examining KOR binding in healthy controls and cocaine abusers reported no significant differences in KOR binding in any brain region examined (Martinez et al 2019).…”

Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System

“…CERC-501, used in phase 1 clinical trials, does not share nor-BNI or JDTic pharmacological properties ( Carroll and Carlezon, 2013 ; Jacobson et al, 2020 ). Nevertheless, this last compound, a KOR antagonist that have low affinities for MOR and DOR ( Banks, 2020 ), failed to attenuate cocaine craving ( Reed et al, 2018 ), or cigarette smoking and craving ( Jones et al, 2020 ).…”